Lipophilic substances possessing low water solubility often have poor oral bioavailability. These substances, being hydrophobic by nature, show wetting difficulties and poor dissolution. These properties obviously represent a rate-limiting step in their absorption from solid oral dosage forms and, in turn, cause a subsequent reduction in their bioavailability.
To address the foregoing issue, these lipophilic substances are usually administered in the form of liquid preparations dissolved in edible oils or formulated in oil-in-water emulsions or microemulsion. Even in these formulations, however, the oral bioavailability of many of them is still very low. Thus, even today, there remains an unresolved need for safe and useful formulations that provide enhanced oral bioavailability for such substances.
Cannabinoids are one example of a family of lipophilic substances with very poor water solubility. Cannabinoids such as .DELTA..sup.1 -tetrahydrocannabinol (.DELTA..sup.1 -THC), .DELTA..sup.6 -tetrahydrocannabinol (.DELTA..sup.6 -THC), .DELTA..sup.9 -tetrahydrocannabinol (.DELTA..sup.9 -THC), cannabinol, cannabidiol, and their metabolites, are highly hydrophobic lipid soluble compounds and can be dissolved in aqueous solutions only in the range of a few micrograms/ml or less, depending upon the conditions (Garret and Hunt, J. Pharm. Sci., 63:1056-1064,1974).
In general, the systemic availability of cannabinoids after oral administration is low and mean estimates of the human bioavailability of tetrahydrocannabinol (THC) following oral ingestion range from 6 to 12% depending on the vehicle used. For example, the maximal plasma levels after oral dosing of 20 mg THC in a sesame oil formulation were around 10 ng/ml (Wall et al., Clin. Pharmacol. Ther. 34:352-363, 1983).
Dexanabinol (also denoted HU-211), is disclosed in U.S. Pat. Nos. 4,876,276 and 5,521,215, as a synthetic non-psychoactive cannabinoid with novel neuroprotective activity in the multiple-action treatment of brain damage associated with stroke, head trauma, and cardiac arrest. The chemical structure of dexanabinol, (+)-(3S, 4S)-7-hydroxy-.DELTA..sup.6 -tetra hydrocannabinol-1,1-dimetylheptyl, is shown in Scheme 1. ##STR1##
Dexanabinol is a very lipophilic compound which is practically insoluble in water (less than 50 .mu.g/ml) and, like other lipophilic drugs, exhibits poor oral bioavailability.
Coenzyme Q10, chemically named 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone and also known by the names Ubiquinone or Vitamin K, is classified as a fat-soluble quinone, a naturally occurring enzyme. It has been identified as an essential component of the mitochondrial respiratory chain, and, thus, a necessary part of a cell's energy production. More particularly, it constitutes a redox-link between flavoproteins and cytochromes and acts as an electron shuttle controlling the efficiency of oxidative phosphorylation. It is a very lipophilic compound and practically insoluble in water due to its long side chain of 10 isoprenoid units.
CoQ10 has been previously identified as a natural antioxidant with potential use as a dietary supplement to protect against age-related degeneration and as an adjuvant vitamin to prevent or treat many disease states.
Supplementary Coenzyme Q10 has reportedly shown beneficial influences in a variety of conditions or diseases, including: periodontal disease, certain blood circulation diseases, impaired memory, fatigue, irregular heartbeat, high blood pressure, immune system impairment, and the aging process.
The recommended daily allowance for coenzyme Q10 has not been determined. Most experts agree, however, that the daily requirement lies somewhere between 30 and 60 milligrams. When treating illnesses, dosages of 100 to 300 milligrams are commonly used.
The oral bioavailability of CoQ10 is related to the dissolution rate of the formulation (Kishi et al., Metabolism of exogenous coenzyme Q10 in vivo and the bioavailability of coenzyme Q10 preparations in Japan, in: K. Folkers, and Y. Yamamura, eds., Biomedical and Clinical Aspects of Coenzyme Q10, Vol. 4, Elsevier, Amsterdam, 1984, pp. 131-142).
Given CoQ10's poor solubility in water, the ability to formulate this substance in a suitable form affording convenient and efficient oral bioavailability is a desired goal. The art has attempted to address the problem by disclosing formulations of Coenzyme Q10 using lipids, in the form of emulsions, liposomes, microparticles and nanoparticles, have previously been disclosed. These known lipid formulations have comprised particles dispersed in an aqueous medium, and are suitable for various routes of administration, including primarily intravenous administration, as disclosed in: WO 95/05164, which discloses microparticles and nanoparticles in aqueous suspension; U.S. Pat. No. 4,824,669, which discloses fatty emulsions; U.S. Pat. No. 4,636,381, which discloses liposomes; and U.S. Pat. No. 4,483,873, which discloses aqueous dispersions or solutions.
The neurohormone melatonin is synthesized in the pineal gland with a nocturnal circadian rhythm. Sleep disorders, seasonal depression, mood disorders, migraine, and jet lag are some of the disorders that have been correlated to a disruption of normal, physiological melatonin secretion. There are reports on the beneficial effect of exogenous melatonin administration to reestablish the synchronization of circadian rhythm. However, these studies have shown large variations in oral melatonin absorption, as well as highlighted the inconvenience of employing a continuous intravenous delivery system. Therefore, an oral formulation of melatonin with good bioavailability is needed. A melatonin buccal mucoadhesive sustained release delivery patch, mimicking endogenous secretion, has already been shown as one alternative means for delivering melatonin (Benes et al., Proceed. Intl. Symp. Control. Rel. Bioact. Mater., 21:551-552, 1994).
Additional examples of lipophilic drugs with very poor water solubility and low oral bioavailability which could benefit from oral dosage forms are the antifungal agent amphotericin B, the anticancer drug etoposide, as well as tamoxifen and its analogs.
Water-dispersible vitamin preparations were disclosed in U.S. Pat. No. 3,102,078, wherein the vitamin E derivative tocopherol polyethyleneglycol succinate (TPGS) was shown to have useful properties as a solubilizing agent. Oily compositions of anti-tumor drugs utilizing TPGS as a solubilizing adjuvant have also been disclosed for instance in U.S. Pat. No. 4,578,391. Further uses of TPGS as a surface active substance (U.S. Pat. No. 4,668,513), as a cryoprotectant (U.S. Pat. No. 5,198,432) or to improve the bioavailability of vitamin E (U.S. Pat. Nos. 5,179,122 and 5,223,268) have also been disclosed. A powder formulation of water dispersible vitamin E compositions for use as a vitamin E supplement has also been disclosed in U.S. Pat. No. 5,234,695.
The structure of TPGS is shown in scheme 2 ##STR2## where n represents the average number of --CH.sub.2 CH.sub.2 O-- groups in the polyethylene glycol chain. For typical polyethylene glycols, n is from about 5.2 (PEG 200) to about 182.4 (PEG 8000). Thus, there remains a need for new formulati provide improved oral bioavailability of such compounds. The present invention provides such formulations.